Aliphatic amine polymer salts for tableting

ABSTRACT

The tablets, compositions and methods of the present invention, comprising a carbonate salt of an aliphatic amine polymer and s monovalent anion can prevent or ameliorate acidosis, in particular acidosis in patients with renal disease. The tablets and compositions of the present invention maintain a disintegration time of no greater than 30 minutes at 37° C. and at pH of at least 1 for a period of at least ten weeks at 60° C. Furthermore, the tablets are stable for extended periods of time without the need for specialized storage conditions.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.14/326,877, filed Jul. 9, 2014, which is a continuation of U.S.application Ser. No. 13/183,079, filed Jul. 14, 2011, now U.S. Pat. No.8,808,738, which is a continuation of U.S. application Ser. No.11/262,291, filed Oct. 27, 2005, now U.S. Pat. No. 7,985,418, whichclaims the benefit of both U.S. Provisional Application No. 60/624,001,filed on Nov. 1, 2004, and U.S. Provisional Application No. 60/628,752,filed on Nov. 17, 2004. The foregoing related applications, in theirentirety, are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Hyperphosphatemia frequently accompanies diseases associated withinadequate renal function, hyperparathyroidism, and certain othermedical conditions. Hyperphosphatemia is typically defined for humans asa serum phosphate level of greater than about 4.5 mg/dL. The condition,especially if present over extended periods of time, leads to severeabnormalities in calcium and phosphorus metabolism and can be manifestedby aberrant calcification in joints, lungs and eyes.

Anion exchange polymers, such as aliphatic amine polymers, have beenused in the treatment of hyperphosphatemia. These polymers provide aneffective treatment for decreasing the serum level of phosphate, withoutconcomitantly increasing the absorption of any clinically undesirablematerials.

Metabolic acidosis is another condition which accompanies diseasesassociated with inadequate renal function. The human body is constantlygaining H⁺ ions from the metabolism of sugars, fats, protein and lacticacid (produced under anaerobic metabolism). To maintain a constant pHthe body must excrete H⁺ ions. Decreased excretion of H⁺ ions occurs inpatients suffering from renal disease or renal failure, which results inmetabolic acidosis and, hence, a low blood pH due to excess H⁺ ions.

Current treatments for hyperphosphatemia do not address the issue ofmetabolic acidosis. The present inventors have prepared carbonate saltsof aliphatic amine polymers for this purpose, however, tablets made fromcarbonate salts of aliphatic amine polymers suffer from short shelflife. Further, the disintegration time of tablets made from carbonatesalts increases over time when stored under standard storage conditions.This increase in disintegration time may lead to decreased availabilityof the active components of the drug to a patient.

SUMMARY OF THE INVENTION

It has now been found that adding a monovalent anion source to tabletsof aliphatic amine carbonates salts significantly increases the shelflife, and prevents the disintegration time from increasing over timewhen the tablets are stored under standard storage conditions. Furtherit has been found that increasing the particle size of the aliphaticamine polymer particles in the tablets significantly increases the shelflife, and prevents the disintegration time from increasing over timewhen the tablets are stored under standard storage conditions.

In one embodiment, the present invention is a tablet comprising acarbonate, bicarbonate, acetate or lactate salt of an aliphatic aminepolymer, wherein said tablet maintains a disintegration time of nogreater than 30 minutes at 37° C. and at a pH of at least 1 when storedfor a period of at least ten weeks at 60° C. Preferably the aliphaticamine polymer is sevelamer.

In another embodiment the present invention is a tablet comprising acarbonate, bicarbonate, acetate or lactate salt of an aliphatic aminepolymer and a monovalent anion source, wherein the monovalent anioncomprises at least 0.05% by weight of the combined weights of thecarbonate salt and the monovalent anion source.

In another embodiment, the present invention is a composition comprisinga carbonate, bicarbonate, acetate or lactate salt of an aliphatic aminepolymer and a monovalent anion source, wherein the monovalent anioncomprises at least 0.05% by weight of the combined weight of thecarbonate salt and the monovalent anion source. Preferably thecomposition is for pharmaceutical use and additionally comprises apharmaceutically acceptable carrier or diluent.

In another embodiment the present invention is a tablet comprisingsevelamer carbonate particles, wherein at least 95% by volume of theparticles have a diameter of at least 45 microns.

In one embodiment the present invention is a method of removingphosphate from a patient in need of such treatment, comprisingadministering to the patient a therapeutically effective amount of atablet, composition or pharmaceutical composition disclosed herein.

The tablets, compositions and methods of the present invention, canprevent or ameliorate acidosis, in particular acidosis in patients withrenal disease. The disintegration time of the tablets and compositionsof the present invention does not increase over time when stored understandard conditions. Furthermore, the tablets are stable for extendedperiods of time without the need for specialized storage conditions.

DETAILED DESCRIPTION OF THE INVENTION

Current treatments for hyperphosphatemia do not address the issues oflow blood pH which often accompanies renal failure. The use of carbonatesalts of aliphatic amine polymers would be useful in addressing thisissue, however, tablets of carbonate salts often suffer from short shelflives and disintegration times which increase over time under standardstorage conditions. It has now been discovered that adding a monovalentanion source to the carbonate salt prevents the increase in thedisintegration time of the tablets and increases the shelf life. It hasalso been discovered that increasing the particle size of the aliphaticamine polymer prevents the increase in the disintegration time of thetablets and increases the shelf life.

In one embodiment the present invention is a tablet comprising acarbonate, bicarbonate, acetate or lactate salt of an aliphatic aminepolymer, wherein said tablet maintains a disintegration time of nogreater than 60 minutes, 45 minutes, 30 minutes, preferably 20 minutes,more preferably 15 minutes, most preferably 10 minutes at 37±2° C. Thedisclosed tablets exhibit these disintegration times over a wide varietyof pH ranges including acidic conditions such as a pH of at least 1,more preferably at a pH range of 1-5, preferably 1-4, more preferably1-3, most preferably 1-2, even more preferably at pH 1.2. Thedisintegration time can be measured using the procedures described inthe United States Pharmacopoeia 27-National Formulary 22 (USP 27-NF 22)which have been adapted according to Example 1. In a preferredembodiment the disintegration time of the tablets remains constant for aperiod of at least 1 week, 2 weeks, 1 month, 5 weeks, 2 months, 10weeks, 3 months, 6 months, 1 year, or two years at 60° C. when stored ina sealed, water impervious container. It is to be understood whenspeaking herein of carbonate salts Applicants' are also referring tobicarbonate, acetate, and lactate salts.

Amine polymers are characterized by a repeat unit that includes at leastone amino group. Amino groups can be part of the polymer backbone (e.g.,a polyalkyleneimine such as polyethyleneimine), pendant from the polymerbackbone (e.g., polyallylamine), or both types of amino groups can existwithin the same repeat unit and/or polymer. Amine polymers includealiphatic amine polymers and aromatic amine polymers.

An aliphatic amine polymer is obtained by polymerizing an aliphaticamine monomer. An aliphatic amine is saturated or unsaturated,straight-chained, branched or cyclic non-aromatic hydrocarbon having anamino substituent and optionally one or more additional substituents. Analiphatic amine monomer is an aliphatic amine comprising a polymerizablegroup such as an olefin. Examples of aliphatic amine polymers includepolymers characterized by one or more repeat units set forth below:

wherein y is an integer of zero, one or more (e.g., between about 1 and10, 1 and 6, 1 and 4 or 1 and 3) and each R, R₁, R₂, and R₃,independently, is H or a substituted or unsubstituted alkyl group (e.g.,having between 1 and 25, preferably between 1 and 5 carbon atoms, suchas aminoalkyl having e.g., between 1 and 5 carbons atoms, inclusive,such as aminoethyl or poly(aminoethyl)) or substituted or unsubstitutedaryl (e.g., phenyl) group, and each X⁻ is independently an exchangeablenegatively charged counterion. Typically, R, R₁, R₂, and R₃ are eachindependently H or a substituted or unsubstituted alkyl group.

In one preferred polymer used in the invention, at least one of the R,R₁, R₂, or R₃ groups is a hydrogen atom. In a more preferred embodiment,each of these groups are hydrogen. In one embodiment, R, R₁, R₂, and R₃are H and the polymer comprises repeat units characterized by StructuralFormulas I-IV, VII and/or VIII.

As an alkyl, or aryl group, R, R₁, R₂, or R₃ can carry one or moresubstituents. Suitable substituents include cationic groups, e.g.,quaternary ammonium groups, or amine groups, e.g., primary, secondary ortertiary alkyl or aryl amines. Examples of other suitable substituentsinclude hydroxy, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl,hydrazine, guanadine, urea, poly(alkyleneimine), such aspoly(ethyleneimine), and carboxylic acid esters.

One example of a preferred aliphatic amine polymer is characterized byone or more repeat units of Structural Formula IX:

or a pharmaceutically acceptable salt thereof, where x is 0 or aninteger between 1 and 4, preferably 1. The polymer represented byStructural Formula IX is advantageously crosslinked by means of amultifunctional cross-linking agent.

Another preferred polymer for use in the invention is polyallylamine,which is a polymer having repeat units from polymerized allyl aminemonomers. The amine group of an allyl monomer can be unsubstituted orsubstituted with, for example, one or two C1-C10 straight chain orbranched alkyl groups. The alkyl groups are optionally substituted withone or more hydroxyl, amine, halo, phenyl, amide or nitrile groups.Preferably, the polyallylamine polymers of the present inventioncomprise repeat units represented by Structural Formula X:

An amine polymer can be a homopolymer or a copolymer of one or moreamine-containing monomers or a copolymer of one or more amine-containingmonomers in combination with one or more different amine containingmonomer or non-amine containing monomers. Copolymers that include one ormore repeat units represented by the above Structural Formulas I-X,contain comonomers that are preferably inert and non-toxic. Examples ofsuitable non-amine-containing monomers include vinyl alcohol, acrylicacid, acrylamide, and vinylformamide.

Also polyallylamine can be a copolymer comprising repeat units from twoor more different polymerized allyl monomers or with repeat units fromone or more polymerized allyl monomers and repeat units from one or morepolymerized non-allyl monomers. Examples of suitable non-allyl monomersinclude acrylamide monomers, acrylate monomers, maleic acid, malimidemonomers, vinyl acylate monomers and alkyl substituted olefines.Preferably, however, the polyallylamines used in the present inventioncomprise repeat units solely from polymerized allyl amine monomers. Morepreferably, the polyallylamine polymers used in the present inventionare homopolymers. Even more preferably, the polyallylamine polymers usedin the present invention are homopolymers of repeat units represented byStructural Formula X or are crosslinked homopolymers thereof.

Preferably, an aliphatic amine polymer is a homopolymer, such as ahomopolyallylamine, homopolyvinylamine, homopolydiallylamine orpolyethyleneamine. The word “amine,” as used herein, includes primary,secondary and tertiary amines, as well as ammonium groups such astrialkylammonium.

Aromatic amine polymers comprise an amine-containing aromatic moiety inone or more of the repeat units. An example of an aromatic amine polymeris poly(aminostyrene).

Amine polymers used in the invention protonated with H₂CO₃ or HCO₃ ⁻.Preferably, less than 40%, less than 30%, less than 20% or less than 10%of the amine groups are protonated. In another embodiment 10% to 70%,20% to 60%, 30 to 50% or 35% to 45% of the amines are protonated (e.g.,approximately 40%), such as Renagel® which is commercially availablefrom Genzyme Corporation.

The preferred polymers employed in the invention are water-insoluble,non-absorbable, optionally cross-linked polyamines. Preferred polymersare aliphatic. Examples of preferred polymers include polyethyleneimine,polyallylamine, polyvinylamine and polydiallylamine polymers. Thepolymers can be homopolymers or copolymers, as discussed above, and canbe substituted or unsubstituted. These and other polymers which can beused in the claimed invention have been disclosed in U.S. Pat. Nos.5,487,888; 5,496,545; 5,607,669; 5,618,530; 5,624,963; 5,667,775;5,679,717; 5,703,188; 5,702,696; 5,693,675; 5,900,475; 5,925,379;6,083,491; 6,177,478; 6,083,495; 6,203,785; 6,423,754; 6,509,013;6,556,407; 6,605,270; and 6,733,780 the contents of which are herebyincorporated herein by reference in their entireties. Polymers suitablefor use in the invention are also disclosed in U.S. application Ser. No.08/823,699 (now abandoned); Ser. No. 08/835,857 (now abandoned); Ser.No. 08/470,940 (now abandoned); Ser. No. 08/927,247 (now abandoned);Ser. Nos. 08/964,498; 09/691,429; 10/125,684; 10/158,207; 10/322,904;10/441,157; and Ser. No. 10/766,638, the contents of which areincorporated herein by reference in their entireties.

Preferably, the polymer is rendered water-insoluble by cross-linkingsuch as with a multifunctional cross-linking agent. The cross-linkingagent is typically characterized by functional groups which react withthe amino group of the monomer. Alternatively, the cross-linking agentcan be characterized by two or more vinyl groups which undergo freeradical polymerization with the amine monomer. The degree ofpolymerization in cross-linked polymers cannot generally be determined.

Examples of suitable multifunctional cross-linking agents includediacrylates and dimethylacrylates (e.g. ethylene glycol diacrylate,propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycoldimethacrylate, propylene glycol dimethacrylate, butylene glycoldimethacrylate, polyethyleneglycol dimethacrylate and polyethyleneglycoldiacrylate), methylene bisacrylamide, methylene bismethacrylamide,ethylene bisacrylamide, ethylene bismethacrylamide, ethylidenebisacrylamide, divinylbenzene, bisphenol A, dimethacrylate and bisphenolA diacrylate. The cross-linking agent can also include acryloylchloride, epichlorohydrin, butanediol diglycidyl ether, ethanedioldiglycidyl ether, succinyl dichloride, the diglycidal ether of bisphenolA, pyromellitic dianhydride, toluene diisocyanate, ethylene diamine anddimethyl succinate.

The level of cross-linking renders the polymers insoluble andsubstantially resistant to absorption and degradation, thereby limitingthe activity of the polymer to the gastrointestinal tract, and reducingpotential side-effects in the patient. The compositions thus tend to benon-systemic in activity. Typically, the cross-linking agent is presentin an amount from about 0.5-35% or about 0.5-25% (such as from about2.5-20% or about 1-10%) by weight, based upon total weight of monomerplus cross-linking agent.

In some cases the polymers are crosslinked after polymerization. Onemethod of obtaining such crosslinking involves reaction of the polymerwith difunctional crosslinkers, such as epichlorohydrin, succinyldichloride, the diglycidyl ether of bisphenol A, pyromelliticdianhydride, toluence diisocyanate, and ethylenediamine. A typicalexample is the reaction of poly(ethyleneimine) with epichlorohydrin. Inthis example the epichlorohydrin (1 to 100 parts) is added to a solutioncontaining polyethyleneimine (100 parts) and heated to promote reaction.Other methods of inducing crosslinking on already polymerized materialsinclude, but are not limited to, exposure to ionizing radiation,ultraviolet radiation, electron beams, radicals, and pyrolysis.

Examples of preferred crosslinking agents include epichlorohydrin, 1,4butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether,1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane,1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluenediisocyanate, acryloyl chloride, and pyromellitic dianhydride.Epichlorohydrin is a preferred crosslinking agent, because of its highavailability and low cost. Epichlorohydrin is also advantageous becauseof its low molecular weight and hydrophilic nature, increasing thewater-swellability and gel properties of the polyamine. Epichlorohydrinforms 2-hydroxypropyl crosslinking groups. In a preferred embodiment,the present invention is a polyallylamine polymer crosslinked withepichlorohydrin.

Typically, between about 9% and about 30% of the allylic nitrogen atomsare bonded to a crosslinking group, preferably between 15% and about21%.

In a preferred embodiment, the polyallylamine polymer used in thepresent invention is polyallylamine crosslinked with about 9.0-9.8% w/wepichlorohydrin, preferably 9.3-9.5% which is known as sevelamer. Thestructure is represented below:

where:

the sum of a and b (the number of primary amine groups) is 9;

c (the number of crosslinking groups) is 1;

n (the fraction of protonated amines) is 0.4; and

m is a large number (to indicate extended polymer network).

Typically, the amount of epichlorohydrin is measured as a percentage ofthe combined weight of polymer and crosslinking agent.

The polymers can also be further derivatized; examples include alkylatedamine polymers, as described, for example, in U.S. Pat. Nos. 5,679,717,5,607,669 and 5,618,530, the teachings of which are incorporated hereinby reference in their entireties. Preferred alkylating agents includehydrophobic groups (such as aliphatic hydrophobic groups) and/orquaternary ammonium- or amine-substituted alkyl groups.

Non-cross-linked and cross-linked polyallylamine and polyvinylamine aregenerally known in the art and are commercially available. Methods forthe manufacture of polyallylamine and polyvinylamine, and cross-linkedderivatives thereof, are described in the above U.S. Patents. Patents byHarada et al. (U.S. Pat. Nos. 4,605,701 and 4,528,347), which areincorporated herein by reference in their entireties, also describemethods of manufacturing polyallylamine and cross-linked polyallylamine.A patent by Stutts et al. (U.S. Pat. No. 6,180,754) describes anadditional method of manufacturing cross-linked polyallylamine.

In other embodiments, the polymer can be a homopolymer or copolymer ofpolybutenylamine, polylysine, or polyarginine. Alternatively, thepolymer can be an aromatic polymer, such as an amine orammonium-substituted polystyrene, (e.g., cholestyramine).

The molecular weight of polymers of the invention is not believed to becritical, provided that the molecular weight is large enough so that thepolymer is non-absorbable by the gastrointestinal tract. Typically themolecular weight is at least 1000. For example the molecular weight canbe from: about 1000 to about 5 million, about 1000 to about 3 million,about 1000 to about 2 million or about 1000 to about 1 million.

As described above, the polymers are protonated and are administered inthe form of a salt. By “salt” it is meant that the nitrogen group in therepeat unit is protonated to create a positively charged nitrogen atomassociated with a negatively charged counterion. Preferably, the salt isa weak acidic salt such as carbonate, bicarbonate, acetate or lactate.

In one embodiment the present invention is a tablet or compositioncomprising a carbonate salt of an aliphatic amine polymer and amonovalent anion source, wherein the monovalent anion comprises at least0.01%, preferably 0.05%, more preferably a range of 0.01% to 2%, 0.05%to 1%, 0.08% to 0.5%, or 0.1% to 0.3% by weight of the combined weightsof the carbonate salt and the monovalent anion source.

The monovalent anion is selected to minimize adverse effects on thepatient. Examples of suitable anions include organic ions, inorganicions, or a combination thereof, such as halides (Cl⁻, I⁻, Fl⁻ and Br⁻),CH₃OSO₃ ⁻, HSO₄ ⁻, acetate, lactate, butyrate, propionate, sulphate,citrate, tartrate, nitrate, sulfonate, oxalate, succinate or palmoate.Preferred anions are halides, most preferably chloride. The monovalentanion is other than HCO₃ ⁻.

In one embodiment, the monovalent anion source is a pharmaceuticallyacceptable acid, ammonium or metal salt of a monovalent anion. Forexample, monovalent anion source can be a lithium, sodium, potassium,magnesium, calcium, aluminium, lanthanide, or actinide salt of amonovalent anion. The monovalent anion source can be ammonium, a mono,di, tri or tetra alkylated ammonium. Any of the above describedmonovalent anions can be combined with any of the metals listed above,of with H⁺. Preferably the monovalent anion source is sodium chloride orhydrochloric acid. In one embodiment, the tablet or compositioncomprises a carbonate salt of sevelamer and sodium chloride. In onepreferred embodiment, the tablet or composition comprises a carbonatesalt of sevelamer and sodium chloride powder. In another preferredembodiment, the tablet or composition comprises a carbonate salt ofsevelamer coated with a sodium chloride solution. In yet anotherembodiment the tablet or composition comprises a carbonate salt ofsevelamer and hydrochloric acid.

In the above described embodiment, the monovalent anion, for example,the chloride ions comprise 0.01%, preferably 0.05%, more preferably arange of 0.01% to 2%, 0.05% to 1%, 0.08% to 0.5%, or 0.1% to 0.3% theweight of the carbonate salt of the aliphatic amine polymer plus theweight of the metal salt or acid, for example the weight of sevelamercarbonate plus the weight of sodium chloride.

In another embodiment, the monovalent anion source is a monovalent anionsalt of an aliphatic amine polymer comprising a repeat unit representedby Structural Formulas I-XI above. The combination of a carbonate saltof an aliphatic amine polymer and a monovalent anion salt of analiphatic amine polymer is defined herein as a “physically mixedpolymer”. The monovalent anion salt of the aliphatic amine polymer canbe the same or a different aliphatic amine polymer as the aliphaticamine polymer carbonate salt. Preferably the monovalent anion salt ofthe aliphatic amine polymer is polyallylamine, more preferably themonovalent anion salt of the aliphatic amine polymer is a homopolymer,most preferably the monovalent anion salt of the aliphatic amine polymeris sevelamer. In a preferred embodiment the monovalent anion source is ahalide salt of sevelamer, more preferably sevelamer chloride, (soldunder the tradename RENAGEL®). In another preferred embodiment themonovalent anion salt of the aliphatic amine polymer is a chloride saltof sevelamer and the aliphatic amine polymer carbonate salt is sevelamercarbonate.

In the above described embodiment the carbonate salt of the aliphaticamine polymer and the monovalent anion salt of the aliphatic aminepolymer are preferably at a molar ratio of 1:2000, 1:500, 1:100, 1:50,1:20, 1:9, 1:6, 1:4, 1:3, 1:2, or 1:1 monovalent anion:carbonate salt,more preferably at a molar ratio of 1:4 monovalent anion:carbonate salt.In this embodiment, the monovalent anion, for example, the chlorideions, comprise at least 0.01%, preferably 0.05%, more preferably at arange 0.01% to 2%, 0.05% to 1%, 0.08% to 0.5%, or 0.1% to 0.3% by weightof the weight of the carbonate salt of the aliphatic amine polymer plusthe weight of the monovalent anion salt of the aliphatic amine polymer,for example, the weight of sevelamer carbonate plus the weight ofsevelamer chloride.

In another embodiment the monovalent anion source is the carbonate saltof an aliphatic amine polymer. In this embodiment, the aliphatic aminepolymer comprises mainly carbonate ions but also further comprises amonovalent anion other than carbonate. In this embodiment the presentinvention is a tablet comprising a mixed carbonate and monovalent anionsalt of an aliphatic amine polymer. The combination of a carbonate saltand a monovalent anion salt on a single aliphatic amine polymer isdefined herein as a “chemically mixed polymer”. The aliphatic aminepolymer comprises repeat units represented by Structural Formulas I-XIabove; preferably the aliphatic amine polymer is sevelamer. Anymonovalent anion described above can be used in this embodiment.Preferably the monovalent anion salt is a halide salt, more preferably achloride salt. Preferably the mixture of carbonate salt to monovalentanion salt is at a molar ratio of monovalent anion:carbonate, of 1:2000,1:500, 1:100, 1:50, 1:20, 1:4, or 1:1. In this embodiment the monovalentanion, for example, the chloride ions, comprise at least 0.01%,preferably 0.05%, more preferably at a range 0.01% to 2%, 0.05% to 1%,0.08% to 0.5%, or 0.1% to 0.3% by weight of the weight of the mixedcarbonate and monovalent anion salt of the aliphatic amine polymer, forexample, the weight of sevelamer with both carbonate and chloride ions.

These chemically mixed polymers can be prepared by adding, for example,aqueous solution of sodium carbonate and/or sodium bicarbonate to anaqueous solution of sevelamer chloride. The ratios of salts to sevelamerchloride may be varied in order to get the desired salt ratio in thechemically mixed polymer. Preferred molar ratios include 1:2000, 1:500,1:100, 1:50, 1:20, 1:4, or 1:1 sevelamer hydrochloride:carbonate.

In another embodiment, the chemically mixed aliphatic amine polymer maybe mixed with a carbonate salt of an aliphatic amine polymer. Thealiphatic amine polymers comprise repeat units represented by StructuralFormulas I-XI above and may be the same or different. Preferably thechemically mixed polymer and the carbonate salt polymer are sevelamer.The preferred anions on the chemically mixed polymer are as describedabove. Preferably the chemically mixed polymer and carbonate polymer areat a molar ratio of chemically mixed salt:carbonate, of 1:2000, 1:500,1:100, 1:50, 1:20, 1:4, or 1:1.

Increasing the particle size of the aliphatic amine polymer particlesresults in an increase in shelf life of the tablets of the presentinvention and prevents the disintegration time of the tablets fromincreasing over time. The particles comprise of an aliphatic aminepolymer, preferably polyallyamine polymer, more preferably ahomopolymer, most preferably sevelamer, and optionally one or moreadditional pharmaceutically acceptable ingredients. In a preferredembodiment the particles comprise at least 80%, preferably at least 90%more preferably at least 95%, most preferably at least 100%, by weightof aliphatic amine polymer.

In one embodiment, the present invention is a tablet comprisingparticles of a carbonate salt of aliphatic amine polymer, preferablypolyallyamine polymer, more preferably sevelamer, most preferablysevelamer carbonate, wherein at least 95% by volume of the particleshave a diameter of at least 45 microns, at least 60 microns, at least 80microns or at least 100 microns.

These aliphatic amine polymer particles may be combined with forexample, an excipient, carrier or diluent, to form the tablets orcompositions of the present invention.

The tablets of the present invention can comprise one or moreexcipients, such as binders, glidants and lubricants, which are wellknown in the art. Suitable excipients include colloidal silicon dioxide,stearic acid, magnesium silicate, calcium silicate, sucrose, cellulose,calcium stearate, glyceryl behenate, magnesium stearate, talc, zincstearate and sodium stearylfumarate, a cellulose derivative such ascarboxymethyl cellulose, microcrystalline cellulose, hydroxypropylcellulose, acacia, tragacanth, pectin, gelatin, polyethylene glycol.Preferably the cellulose derivative is microcrystalline cellulose, morepreferably Ceolus® (Asahi Kasei Chemicals Corporation).

The tablets of the invention are prepared by a method comprising thesteps of:

-   -   (1) hydrating or drying the aliphatic amine polymer to the        desired moisture level;    -   (2) blending the aliphatic amine polymer with any excipients to        be included; and    -   (3) compressing the blend using conventional tableting        technology.

The tablet is optionally coated, i.e., the aliphatic amine polymer andexcipients form a core surrounded by a coating. In one embodiment, thecoating composition comprises a cellulose derivative and a plasticizingagent. The cellulose derivative is, preferably,hydroxypropylmethylcellulose (HPMC). The cellulose derivative can bepresent as an aqueous solution. Suitable hydroxypropylmethylcellulosesolutions include those containing HPMC low viscosity and/or HPMC highviscosity. Additional suitable cellulose derivatives include celluloseethers useful in film coating formulations. The plasticizing agent canbe, for example, an acetylated monoglyceride such as diacetylatedmonoglyceride, The coating composition can further include a pigmentselected to provide a tablet coating of the desired color. For example,to produce a white coating, a white pigment can be selected, such astitanium dioxide.

In one embodiment, the coated tablet of the invention can be prepared bya method comprising the step of contacting a tablet core of theinvention, as described above, with a coating solution comprising asolvent, at least one coating agent dissolved or suspended in thesolvent and, optionally, one or more plasticizing agents. Preferably,the solvent is an aqueous solvent, such as water or an aqueous buffer,or a mixed aqueous/organic solvent. Preferred coating agents includecellulose derivatives, such as hydroxypropylmethylcellulose. Typically,the tablet core is contacted with the coating solution until the weightof the tablet core has increased by an amount ranging from about 3% toabout 6%, indicating the deposition of a suitable coating on the tabletcore to form a coated tablet.

In one preferred embodiment, the solids composition of the coatingsolution is:

Material % W/W HPMC low viscosity Type 2910, cUSP 38.5% HPMC highviscosity Type 2910, cUSP 38.5% diacetylated monoglyceride 23.0%

Tablets may be coated in a rotary pan coater as is known in the art orany other conventional coating apparatus such as a column coater or acontinuous coater.

The present invention also encompasses pharmaceutical compositions otherthan tablets. These pharmaceutical compositions comprise apharmaceutically acceptable carrier or diluent and a carbonate salt ofan aliphatic amine polymer and a monovalent anion source as describedabove. Preferably the monovalent anion source comprises at least 0.01%,preferably 0.05%, more preferably at a range 0.01% to 2%, 0.05% to 1%,0.08% to 0.5%, or 0.1% to 0.3% by weight of the combined weight of thecarbonate salt and the monovalent anion source.

The aliphatic amine polymers, tablets and compositions of the presentinvention are preferably administered orally. They can be administeredto the subject alone or in a pharmaceutical composition, and optionally,one or more additional drugs. The pharmaceutical compositions of theinvention preferably contain a pharmaceutically acceptable carrier ordiluent suitable for rendering the compound or mixture administrableorally. The active ingredients may be admixed or compounded with aconventional, pharmaceutically acceptable carrier or diluent. It will beunderstood by those skilled in the art that any mode of administration,vehicle or carrier conventionally employed and which is inert withrespect to the active agent may be utilized for preparing andadministering the pharmaceutical compositions of the present invention.Illustrative of such methods, vehicles and carriers are those described,for example, in Remington's Pharmaceutical Sciences, 18th ed. (1990),the disclosure of which is incorporated herein by reference.

The formulations of the present invention for use in a subject comprisethe agent, together with one or more acceptable carriers or diluentstherefore and optionally other therapeutic ingredients. The carriers ordiluents must be “acceptable” in the sense of being compatible with theother ingredients of the formulation and not deleterious to therecipient thereof. The formulations can conveniently be presented inunit dosage form and can be prepared by any of the methods well known inthe art of pharmacy. All methods include the step of bringing intoassociation the agent with the carrier or diluent which constitutes oneor more accessory ingredients. In general, the formulations are preparedby uniformly and intimately bringing into association the agent with thecarriers and then, if necessary, dividing the product into unit dosagesthereof.

Those skilled in the art will be aware that the amounts of the variouscomponents of the compositions of the invention to be administered inaccordance with the method of the invention to a subject will dependupon those factors noted above.

The compositions of the invention can be formulated as a tablet, sachet,slurry, food formulation, troche, capsule, elixir, suspension, syrup,wafer, chewing gum or lozenge. A syrup formulation will generallyconsist of a suspension or solution of the compound or salt in a liquidcarrier, for example, ethanol, glycerine or water, with a flavoring orcoloring agent. Where the composition is in the form of a tablet, one ormore pharmaceutical carriers routinely used for preparing solidformulations can be employed. Examples of such carriers includemagnesium stearate, starch, lactose and sucrose. Where the compositionis in the form of a capsule, the use of routine encapsulation isgenerally suitable, for example, using the aforementioned carriers in ahard gelatin capsule shell. Where the composition is in the form of asoft gelatin shell capsule, pharmaceutical carriers routinely used forpreparing dispersions or suspensions can be considered, for example,aqueous gums, celluloses, silicates or oils, and are incorporated in asoft gelatin capsule shell.

The aliphatic amine polymers, tablets and compositions can beadministered as multiple dosage units or as a single dosage unit. Asused herein a dosage unit may be a tablet, sachet, slurry, foodformulation, troche, capsule, elixir, suspension, syrup, wafer, chewinggum or the like prepared by art recognized procedures. Preferably adosage unit is a tablet, capsule, sachet, slurry, suspension or foodformulation, more preferably the dosage unit is a tablet, slurry,suspension or food formulation, most preferably the dosage unit is atablet or sachet. Typically, the desired dose of an aliphatic aminepolymer is administered as multiple tablets or capsules, or a singledose of a sachet, slurry, food formulation, suspension or syrup.

In one example, the dosage unit is an oval, film coated, compressedtablet containing either 800 mg or 400 mg of sevelamer on an anhydrousbasis. The inactive ingredients are sodium chloride, zinc stearate,Ceolus®, hypromellose, and diacetylated monoglyceride. In yet anotherembodiment, the dosage unit is a hard-gelatin capsule containing 403 mgof sevelamer on an anhydrous basis. The inactive ingredients are sodiumchloride, zinc stearate, Ceolus®, hypromellose, and diacetylatedmonoglyceride.

The aliphatic amine polymers, tablets and compositions of the presentinvention are preferably administered with meals.

The methods of the invention involve treatment of patients withhyperphosphatemia. Elevated serum phosphate is commonly present inpatients with renal insufficiency, hypoparathyroidism,pseudohypoparathyroidism, acute untreated acromegaly, overmedicationwith phosphate salts, and acute tissue destruction as occurs duringrhabdomyolysis and treatment of malignancies.

As used herein a subject is a mammal, preferably a human, but can alsobe an animal in need of veterinary treatment, such as a companion animal(e.g., dogs, cats, and the like), a farm animal (e.g., cows, sheep,pigs, horses, and the like) or a laboratory animal (e.g., rats, mice,guinea pigs, and the like).

A therapeutically effective amount of compound is that amount whichproduces a result or exerts an influence on the particular conditionbeing treated. As used herein, a therapeutically effective amount of aphosphate binder means an amount which is effective in decreasing theserum phosphate levels of the patient to which it is administered.

Typical dosages of phosphate binders range from about 5 milligrams/dayto about 10 grams/day, preferably from about 50 milligrams/day to about9 grams/day, more preferably from about 1 gram/day to about 8 grams/day,even more preferably about 2 grams to about 7 grams, most preferablyabout 4 grams/day to about 6 grams/day. The phosphate binders of thepresent invention can be administered at least four times per day withmeals, at least three times per day with meals, at least twice per daywith meals, at least once per day with meals, (see U.S. ProvisionalApplication No. 60/623,985 the entire contents of which are incorporatedherein by reference).

EXEMPLIFICATION Example 1

Better Compactibility and Disintegration Time of Mixed Aliphatic AmineCarbonate Salt and Monovalent Anion Formulation as Compared to theFormulation Containing Sevelamer Carbonate Alone.

The term “physically mixed salt” refers to dry blending of sevelamer HCland sevelamer carbonate API (2 compounds). The total chloride wastargeted to be in the range of 4 to 6%.

Based on the ratios of sevelamer hydrochloride to sevelamer carbonateused, the % LOD for the final mixture of sevelamer hydrochloride andsevelamer carbonate was calculated. For the wetting of the mixture totarget % loss on drying (LOD), the sevelamer hydrochloride API,sevelamer carbonate API and Ceolus® were added directly to the Diosna (ahigh shear wetting equipment/granulator). The blend was mixed for 3minutes using the impeller rotating at 435 rpm. Purified water was thenadded to the blend using a spray bottle to achieve the target LOD in aDiosna Granulator over a 20 minute mixing period. The blend was mixedfor an additional 3 minutes at an impeller speed of 435 rpm. The blendwas transferred from the Diosna bowl to a double lined plastic bag thatwas then securely closed and stored in a plastic container. The wettedblend was allowed to equilibrate for 24 hours.

After 24 hours, the required quantities of wetted material and lubricantwere weighed. The wetted material was screened using a co-mill fittedwith a 600-micron screen with the impeller rotating at 2500 rpm. Aportion of wetted blend was bag-blended with appropriate lubricant,passed through a 600-micron screen and a second portion of wettedsevelamer was passed through the 600-micron screen. The wetted blend andlubricant were then blended in a V-blender for 115 revolutions.

The powder blend was compressed into tablets using a rotary tablet press(Jenn-Chiang Machinery Co. Ltd., (JCMCO)) adjusted to meet the targetweight and hardness. The press was set up with 1 station of B presstooling which has the same surface area as the commercial tooling(0.405′×0.748″). The tablets were compressed using different compressionparameters. An average compactibility (ratio of tablet hardness over themain compression force used on the tablet press) was determined fromthese conditions. The tablets were dedusted. This process was generallydone at 0.5 to 1.5 kg scale.

The disintegration testing of the tablets was performed in simulatedgastric fluid USP without enzymes having a pH of 1.2 (0.1N HCl). Thedetails of the disintegration apparatus and procedure followed aredescribed below.

Disintegration Testing Apparatus (USP27/NF22):

The apparatus consisted of a basket-rack assembly, a 1000-ml beaker, athermostatic arrangement for heating the fluid between 35° C. and 39°C., and a device for raising and lowering the basket in the immersionfluid at a constant frequency rate between 29 and 32 cycles per minute.

The basket-rack assembly consisted of six open-ended transparent tubes.The tubes were held in a vertical position by two plastic plates withsix holes equidistant from the center of the plate and equally spacedfrom one another. Attached to the under surface of the lower plate was awoven stainless steel wire cloth which had plain square weave with 1.8to 2.2 mm mesh apertures and with a wire diameter of 0.63±0.03 mm. A10-mesh screen was also put on the top of the basket to avoid the tabletfrom coming out during the disintegration testing. A suitable means wasprovided to suspend the basket-rack assembly from the raising andlowering device using a point on its axis.

Testing Procedure:

The simulated gastric fluid USP without enzymes having a pH of 1.2 (0.1NHCl) (900 ml) was placed in the 1000 ml beaker and heated to 37° C.using the water bath of the disintegration apparatus. Two tablets weretested by putting each one in separate tubes of the basket-rack assemblyand a 10 mesh screen was placed on the top to prevent the tablets fromcoming out. The lowering and raising device was turned on and thetablets were observed for the rupture time (i.e. the time when thecoating on the tablet first ruptures and polymer starts coming out) anddisintegration time (i.e. the time when the tablet disintegratescompletely and comes out from the tube of the basket-rack assembly).

The physically mixed salt formulations containing sevelamerhydrochloride and sevelamer carbonate Active Pharmaceutical Ingredient(API) were evaluated. The data suggested that physically mixed saltformulation had better compactibility and disintegration time ascompared to the formulation containing sevelamer carbonate API only (seeTable 1). The disintegration time for the tablets manufactured using thephysically mixed salt approach was significantly faster as compared tothe formulation containing sevelamer carbonate API only.

TABLE 1 Comparison of sevelamer carbonate vs physical mixture approachesDisintegration Time (minutes) of Core Tablets stored at 60 C. Performedin pH 1.2 with disk and screen Sevelamer Av- Av- Av- hydro- SevelamerSev. HCl: Av- erage erage erage % % % Lubricant % chloride carbonateSev. CO3 Hardness erage 1 2 3 Approach LOD Ceolus CSD used Lubricant lot# lot # wt. Ratio (N) t = 0 week weeks weeks Sevelamer 10.5 14 0.25Glyceryl 1.2 NA 2418344 NA 431 3.2 32.4 34.8 36.8 Carbonate dibehenateOnly Physically 8 0 0.375 Stearic 0.4 2448260 2418344 1 to 3 386 2.5 2.72.4 2.4 mixed acid 327 ND ND ND ND Physically 8 0 0.375 Stearic 0.42448260 2418344 1 to 6 98 1.7 ND 0.7 1.4 mixed acid 8 0 0.375 Stearic0.4 2448260 2418344 1 to 9 90 2.3 ND ND 2.2 acid

The above results show that the physically mixed salt formulation canprovide desirable compactibility and the disintegration times remainmore stable over time compared to formulation containing sevelamercarbonate only.

Example 2

Effect of Various Ratios of Sevelamer HCl to Sevelamer Carbonate onCompactibility, Ejection Forces and Disintegration Times.

The sevelamer hydrochloride to sevelamer carbonate ratios of 1:1, 1:3,1:6 and 1:9 were evaluated using the excipients used in the Renagel®formulation (800 mg active API, 8% target LOD, 0.375% colloidal silicondioxide and 0.4% stearic acid) (see Table 2). All experiments werecarried out as described above for Example 1

TABLE 2 Effect of various ratios of sevelamer HCl to sevelamer carbonateon disintegration times. Formulation: 8% LOD, No Ceolus, 0.375%Colloidal silicon dioxide (CSD), 0.4% stearic acid Disintegration Time(minutes) of Core Tablets stored at 60 C. Performed in pH 1.2 with diskand screen Av- Av- Av- Sev. HCl: Compact- Av- erage erage erage Sev. CO3PC CF- ibility erage 1 2 3 wt. Ratio (kN) (kN) (N/kN) t = 0 week weeksweeks 1 to 1 15 19 15.9 0.8 1.9 1.3 1.3 1 to 3 15 44 8.7 2.5 2.7 2.4 2.41 to 6 15 45 2.2 1.7 ND 0.7 1.4 1 to 9 15 45 2.0 2.3 ND ND 2.2 ND: Notdetermined, PC: Precompression force; CF: Compression Force;Disintegration testing, n = 2

Based on the above studies, it can be seen that the disintegration timeis maintained in a pharmaceutically acceptable range with all the ratiosof chloride to carbonate salts evaluated.

Example 3

Comparison of Physically Mixed Salts with Chemically Mixed Salts

All experiments were carried out as described above for Example 1. Ascan be seen from Table 3 the chemically mixed salt also resulted inpharmaceutically acceptable disintegration times.

The chemically mixed salt were prepared by adding sevelamerhydrochloride to an aqueous solution of sodium carbonate and sodiumbicarbonate.

TABLE 3 Comparison of physically mixed and chemically mixed saltDisintegration Time (minutes) of Core Tablets stored at 60 C. Performedin pH 1.2 with disk and screen Sevelamer Av- Av- Av- hydro- SevelamerAv- erage erage erage % % Lubricant % chloride carbonate % Hardnesserage 1 2 3 Approach LOD Ceolus used Lubricant lot # lot # Chloride (N)t = 0 week weeks weeks Physically 10.5 5 PRUV 0.5 2448260 2416344 4 4881.1 24 2.8 3.3 mixed Chemically 10.5 5 PRUV 0.5 NA NA 5 305 12.1 11.311.2 11.5 mixed Physically 10.5 5 Zinc 0.5 2448260 2416344 4 488 1.0 4.44.9 5.2 mixed stearate Chemically 10.5 5 Zinc 0.5 NA NA 5 116 7.1 6.7 66.2 mixed stearate

Example 4

Comparison of Sevelamer Carbonate with Sodium Chloride and withoutSodium Chloride

All experiments were carried out as described above for Example 1. Ascan be seen from Table 4 the disintegration time increased much more inthe case for sevelamer carbonate without sodium chloride.

TABLE 4 Comparison of sevelamer carbonate with sodium chloride andwithout sodium chloride Disintegration Time (minutes) of Core Tabletsstored at 60 C. Performed in pH 1.2 with disk and screen Av- Av- Av-Sevelamer Av- erage erage erage % % Lubricant carbonate Hardness erage 12 3 Approach LOD Ceolus used lot # (N) t = 0 week weeks weeks No 10.5 14Sodium 2416570 194 2.7 24.2 ND 29.5 sodium stearyl chloride fumerate0.25% 10.5 15 Sodium 2416344 352 3.9 8.8 9.4 13.4 Sodium stearylchloride fumerate

From the above studies, it was determined that addition of sodiumchloride to sevelamer carbonate significantly decreases the increase inthe disintegration time.

Example 5

Effect of Particle Size Cut on the Disintegration Behavior andCompactibility

Different particle sizes were compared for the effect on compactibilityand disintegration time using a formulation of: 6.5% LOD (“as is” APImoisture), 25% Ceolus® KG 802, 1.2% Glyceryl dibehenate, No Colloidalsilicon dioxide (CSD), (API: 20% carbonate). All experiments werecarried out as in Example 1. The compression conditions were:precompression force: 15 kN, compression force: 45 kN, and speed: 20rpm. The results can be seen in Table 5.

TABLE 5 Effect of particle size cut on the disintegration behavior andcompactibility. Disintegration time (minutes) Lab Particle Ejection ofcore tablets stored notebook size cuts force Compact at 60 C. Performedin number (micron) (N) (N/kN) pH 1.2 with disk and screen 0495-200 “Asis” 316 8.2 2.6 12.6 15.0 15.0 API 0484-170 >53 326 8.2 1.9 ND 6.3 7.20484-171 >75 316 6.9 1.8 ND 5.5 6.2 0484-172 >90 320 6.3 1.5 ND 4.9 5.50484-138 >106 330 5.8 1.0 4.4 5.2 4.5

The above results show that the formulations with increased particlesizes maintain a more stable disintegration time over time compared toformulations with smaller particles sizes.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A tablet, comprising: i) sevelamer carbonate; ii)sodium chloride, wherein the amount of chloride of the sodium chloridepresent in the tablet is in a range of between 0.1-1 wt. %, relative tothe combined weights of the sevelamer carbonate and the sodium chloride;and iii) optionally, one or more excipients; wherein the tablet has adisintegration time of no greater than 60 minutes at a temperature of37±2° C.
 2. The tablet of claim 1, wherein the tablet comprisesparticles of the sevelamer carbonate.
 3. The tablet of claim 2, whereinat least 95% by volume of the sevelamer carbonate particles have adiameter of at least 45 microns.
 4. The tablet of claim 1, wherein thedisintegration time of said tablet is maintained for a period of atleast 1 week, 2 weeks, 1 month, 5 weeks, 2 months, 10 weeks, 3 months, 6months, 1 year, or two years, when stored in a sealed, water imperviouscontainer, at 60° C.
 5. The tablet of claim 1, wherein the tabletmaintains the disintegration time at a temperature of 37±2° C. and a pHrange in the range of between 1-5.
 6. The tablet of claim 1, wherein thetablet comprises 400 mg or 800 mg of the sevelamer carbonate on ananhydrous basis.
 7. The tablet of claim 1, wherein the optional one ormore excipients is(are) present in said tablet.
 8. The tablet of claim1, wherein the one or more excipients includes binders, glidants, andlubricants.
 9. The tablet of claim 1, wherein the one or more excipientsincludes hypromellose.
 10. The tablet of claim 1, wherein the one ormore excipients includes diacetylated monoglyceride.
 11. The tablet ofclaim 1, wherein the one or more excipients includes colloidal silicondioxide.
 12. The tablet of claim 1, wherein the one or more excipientsincludes stearic acid.
 13. The tablet of claim 1, wherein the one ormore excipients includes zinc stearate.
 14. The tablet of claim 1,wherein the one or more excipients includes carboxymethyl cellulose. 15.The tablet of claim 1, wherein the one or more excipients includesmicrocrystalline cellulose.
 16. The tablet of claim 1, wherein the oneor more excipients includes hydroxylpropyl cellulose.
 17. The tablet ofclaim 1, wherein the tablet is coated with a coating compositioncomprising hydroxypropylmethylcellulose and optionally a plasticizingagent.
 18. The tablet of claim 1, wherein the tablet is coated with acoating composition comprising hydroxypropylmethylcellulose anddiacetylated monoglyceride.
 19. The tablet of claim 1, wherein thetablet is an oval, film coated, compressed tablet.
 20. A method oftreating hyperphosphatemia in a patient in need thereof, comprisingadministering the tablet of claim
 1. 21. The tablet of claim 4, whereinthe disintegration time of said tablet is no greater than 20 minutes ata temperature of 37±2° C., and said disintegration time of said tabletis maintained for a period of at least 1 week, when stored in a sealed,water impervious container, at 60° C.